GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Autor:	Arndt Rolfs, Douglas R. Smith, Hongjie Yuan, Markus Wolff, Eirik Frengen, Sarah E Parisotto, Mark A. Tarnopolsky, John Millichap, Katherine L. Helbig, Christian Korff, Lutz Dondit, Anna-Elina Lehesjoki, Alison M. Muir, Brad T. Tinkle, Heather C Mefford, Bodo Laube, Anne T. Berg, Wen-Hann Tan, Kelly L. Jones, Floor E. Jansen, Christine M. Stanley, Candace T. Myers, Isabelle De Bie, John A. Lawson, Henrike O. Heyne, Wenjuan Chen, David Neal Franz, Julie R. Jones, Elysa J. Marco, Nataliya Di Donato, Cyril Mignot, Jasper J. van der Smagt, Stephen F. Traynelis, Tarja Linnankivi, Tim M. Strom, Hirofumi Kusumoto, Rena Vanzo, Petter Strømme, Uffe Birk Jensen, Amy Lacroix, Darius J Adams, Chun Hu, Boris Keren, Sha Tang, Richard J. Leventer, Johannes R. Lemke, Levinus A. Bok, Helio Pedro, Rami Abou Jamra, Dianalee McKnight, Ethan M. Goldberg, Tony Roscioli, Lauren Brady, Konrad Platzer, Philippe Major, Amy Decker, Anup D. Patel, Marcia C. Willing, Ingrid E. Scheffer, Mark Mintz, Eva H. Brilstra, Carolina Courage, Lynette G. Sadleir, Alexander Winschel, William B. Dobyns, Stephanie Fox, Emmanuelle Ranza, Saskia Biskup, Dennis Döcker, Judith D. Ranells, Rikke S. Møller, Elaine H. Zackai, Hannah Schütz, Mieke M. van Haelst, Christel Depienne
Přispěvatelé:	Medicum, Research Programme for Molecular Neurology, Department of Medical and Clinical Genetics, Research Programs Unit, Neuroscience Center, Anna-Elina Lehesjoki / Principal Investigator, University of Helsinki, Children's Hospital, Clinicum, Lastenneurologian yksikkö, HUS Children and Adolescents, Amsterdam Reproduction & Development (AR&D), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics
Rok vydání:	2017
Předmět:	0301 basic medicine INTELLECTUAL DISABILITY Brain Diseases/drug therapy/genetics Pathogenic GRIN2B mutations AUTISM SPECTRUM DISORDERS Cortical visual impairment Bioinformatics Clustering of missense variants 3124 Neurology and psychiatry Epilepsy 0302 clinical medicine Channelopathy NMDA RECEPTORS Receptors Intellectual disability Polymicrogyria Genetics(clinical) Molecular Targeted Therapy Genetics (clinical) ddc:618 biology Epileptic encephalopathy Precision medicine 1184 Genetics developmental biology physiology Magnetic Resonance Imaging Memantine/therapeutic use Hypotonia 3. Good health N-Methyl-D-Aspartate/antagonists & inhibitors/genetics/metabolism Phenotype medicine.symptom Heterozygote GENES Mutation/genetics MIGRATION Clustering Of Missense Variants Epileptic Encephalopathy Pathogenic Grin2b Mutations Precision Medicine Encephalopathy Neuroimaging Article 03 medical and health sciences Journal Article Genetics medicine Humans NEURODEVELOPMENTAL DISORDERS business.industry 3112 Neurosciences medicine.disease INDIVIDUALS 030104 developmental biology DE-NOVO MUTATIONS FOCAL EPILEPSY SUBUNIT biology.protein Autism GRIN2B 3111 Biomedicine business 030217 neurology & neurosurgery
Zdroj:	Journal of Medical Genetics, 54(7), 460. BMJ Publishing Group Journal of Medical Genetics, 54(7), 460-470. BMJ Publishing Group J. Med. Genet. 54, 460-470 (2017) Platzer, K, Yuan, H, Schuetz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, H O, Helbig, K L, Tang, S, Willing, M C, Tinkle, B T, Adams, D J, Depienne, C, Keren, B, Mignot, C, Frengen, E, Stromme, P, Biskup, S, Doecker, D, Strom, T M, Mefford, H C, Myers, C T, Muir, A M, LaCroix, A, Sadleir, L, Scheffer, I E, Brilstra, E, van Haelst, M M, van der Smagt, J J, Bok, L A, Moller, R S, Jensen, U B, Millichap, J J, Berg, A T, Goldberg, E M, De Bie, I, Fox, S, Major, P, Jones, J R, Zackai, E H, Abou Jamra, R, Rolfs, A, Leventer, R J, Lawson, J A, Roscioli, T, Jansen, F E, Ranza, E, Korff, C M, Lehesjoki, A-E, Courage, C, Linnankivi, T, Smith, D R, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, W-H, Tarnopolsky, M A, Brady, L I, Wolff, M, Dondit, L, Pedro, H F, Parisotto, S E, Jones, K L, Patel, A D, Franz, D N, Vanzo, R, Marco, E, Ranells, J D, Di Donato, N, Dobyns, W B, Laube, B, Traynelis, S F & Lemke, J R 2017, ' GRIN2B encephalopathy : novel findings on phenotype, variant clustering, functional consequences and treatment aspects ', Journal of Medical Genetics, vol. 54, no. 7, pp. 460-470 . https://doi.org/10.1136/jmedgenet-2016-104509 Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, H O, Helbig, K L, Tang, S, Willing, M C, Tinkle, B T, Adams, D J, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, T M, Mefford, H C, Myers, C T, Muir, A M, LaCroix, A, Sadleir, L, Scheffer, I E, Brilstra, E, van Haelst, M M, van der Smagt, J J, Bok, L A, Møller, R S, Jensen, U B, Millichap, J J, Berg, A T, Goldberg, E M, De Bie, I, Fox, S, Major, P, Jones, J R, Zackai, E H, Abou Jamra, R, Rolfs, A, Leventer, R J, Lawson, J A, Roscioli, T, Jansen, F E, Ranza, E, Korff, C M, Lehesjoki, A E, Courage, C, Linnankivi, T, Smith, D R, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, W H, Tarnopolsky, M A, Brady, L I, Wolff, M, Dondit, L, Pedro, H F, Parisotto, S E, Jones, K L, Patel, A D, Franz, D N, Vanzo, R, Marco, E, Ranells, J D, Di Donato, N, Dobyns, W B, Laube, B, Traynelis, S F & Lemke, J R 2017, ' GRIN2B encephalopathy : Novel findings on phenotype, variant clustering, functional consequences and treatment aspects ', Journal of Medical Genetics, vol. 54, no. 7, pp. 460-470 . https://doi.org/10.1136/jmedgenet-2016-104509 Journal of Medical Genetics, Vol. 54, No 7 (2017) pp. 460-470 Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, H O, Helbig, K L, Tang, S, Willing, M C, Tinkle, B T, Adams, D J, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, T M, Mefford, H C, Myers, C T, Muir, A M, LaCroix, A J, Sadleir, L G, Scheffer, I E, Brilstra, E, van Haelst, M M, van der Smagt, J J, Bok, L A, Møller, R S, Jensen, U B, Millichap, J J, Berg, A T, Goldberg, E M, De Bie, I, Fox, S, Major, P, Jones, J R, Zackai, E H, Abou Jamra, R, Rolfs, A, Leventer, R J, Lawson, J A, Roscioli, T, Jansen, F E, Ranza, E, Korff, C M, Lehesjoki, A-E, Courage, C, Linnankivi, T, Smith, D R, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, W-H, Tarnopolsky, M A, Brady, L I, Wolff, M, Dondit, L, Pedro, H F, Parisotto, S E, Jones, K L, Patel, A D, Franz, D N, Vanzo, R, Marco, E, Ranells, J D, Di Donato, N, Dobyns, W B, Laube, B, Traynelis, S F & Lemke, J R 2017, ' GRIN2B encephalopathy : novel findings on phenotype, variant clustering, functional consequences and treatment aspects ', Journal of Medical Genetics, vol. 54, no. 7, pp. 460-470 . https://doi.org/10.1136/jmedgenet-2016-104509
ISSN:	1468-6244 0022-2593
DOI:	10.1136/jmedgenet-2016-104509
Popis:	BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::edfc4236ee8b7ba9c88542cfdf4fb25f https://doi.org/10.1136/jmedgenet-2016-104509 Zobrazit plný text záznamu